Plourde Jr., Robert (Chapel Hill, NC, US)
Shaver, Sammy R. (Chapel Hill, NC, US)
Douglass III, James G. (Apex, NC, US)
Watson, Paul S. (Carrboro, NC, US)
Boyer, José L. (Chapel Hill, NC, US)
Tu, Chi (San Diego, CA, US)
Abreo, Melwyn A. (Jamul, CA, US)
Alfaro-lopez, Lorenzo J. (San Marcos, CA, US)
Feng, Yangbo (Palm Beach Gardens, FL, US)
Harvey, Daniel F. (San Diego, CA, US)
Khasonova, Tatyana V. (San Diego, CA, US)

11/124619

02/26/2008

05/05/2005

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Inspire Pharmaceuticals, Inc. (Durham, NC, US)

514/46

A01N43/04; A61K31/70; C07H19/16

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5747496	Inhibitors of platelet aggregation	May, 1998	Cox et al.	514/258
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6369064	Triazolo(4,5-d)pyrimidine compounds	April, 2002	Brown et al.	514/258
6767910	Triazolo&lsqb 4,5-d&rsqb pyrimidinyl compounds	July, 2004	Teobald	514/261.1
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20050267134	Non-nucleotide composition and method for inhibiting platelet aggregation	December, 2005	Plourde et al.	514/263.22

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WO/1999/005143	February, 1999			NOVEL COMPOUNDS
WO/1999/005144	February, 1999			NOVEL COMPOUNDS
WO/1999/006053	February, 1999			N?6¿-SUBSTITUTED-ADENOSINE-5'-URONAMIDES AS ADENOSINE RECEPTOR MODULATORS
WO/1999/041254	August, 1999			NOVEL TRIAZOLO(4,5-$i(d))PYRIMIDINE COMPOUNDS
WO/2000/004021	January, 2000			NOVEL TRIAZOLO[4,5-$i(d)]PYRIMIDINE COMPOUNDS
WO/2000/033080	June, 2000			NEW ASSAY
WO/2001/036438	May, 2001			NOVEL RIBOSE COMPOUNDS
WO/2001/040243	June, 2001			PARTIAL OR FULL A¿1? AGONISTS - N?6¿ HETEROCYCLIC 5'-THIO SUBSTITUTED ADENOSINE DERIVATIVES
WO/2001/040246	June, 2001			PARTIAL OR FULL A¿1? AGONISTS - N?6¿ HETEROCYCLIC 5'-THIO SUBSTITUTED ADENOSINE DERIVATIVES
WO/2001/094368	December, 2001			2-AMINOCARBONYL-9H-PURINE DERIVATIVES
WO/2002/016381	February, 2002			COMPOSITION AND METHOD FOR INHIBITING PLATELET AGGREGATION
WO/2002/096428	December, 2002			PHARMACEUTICAL COMBINATIONS

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Jiang, Shaojia Anna

Bland, Layla

Howrey LLP
Kung, Viola T.

This application is a continuation-in-part of U.S. application Ser. No. 10/971,766, filed Oct. 21, 2004, which claims priority to U.S. provisional application No. 60/513,845 filed Oct. 21, 2003. The contents of both applications are incorporated herein by reference in their entirety.

What is claimed:

1. A method of treating diseases or conditions associated with increased platelet aggregation, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of Formula III, or a pharmaceutically acceptable hydrate, solvate or salt thereof, wherein said amount is effective to inhibit platelet aggregation: wherein R_a=R_c=H; R_b is selected from the group consisting of: hydrogen, C_1-8 alkyl, C_1-8 alkenyl, C_1-8 alkynyl, C_3-7 cycloalkyl, C_4-7 cycloalkenyl, aralkyl, and aryl, where all rings or chains optionally bear one or more substituents; R_d and R_d′ are independently selected from the group consisting of: H, C_1-8 alkyl, C_1-8 alkenyl, C_1-8 alkynyl, and C_3-7 cycloalkyl; R_e is absent; R_f and R_g are independantly selected from the group consisting of: —H, halogen, C_1-8 alkyl, C_1-8 alkenyl, C_1-8 alkynyl, and C_3-7 cycloalkyl; R_h is H, alkyl, aryl, or aralkyl; G is O; J is carbon; A₁ is O; D is O; X₁ is selected from the group consisting of: N and C-M; and M is independently selected from the group consisting of: —H, halogen, —CF₃, C_1-8 alkyl, cyano, C_1-8 alkenyl, C_1-8 alkynyl, C_3-7 cycloalkyl, C_3-7 cycloalkenyl, —OH, saturated or unsaturated C_1-6 alkoxy, amino, —N-substituted amino, and N,N-disubstituted amino.

2. The method according to claim 1, wherein said compound reversibly inhibits ADP-induced platelet aggregation.

3. The method according to claim 1, wherein said compound is administered in combination with other antiplatelet and/or anticoagulant drugs.

4. The method according to claim 1, wherein said diseases associated with platelet aggregation are disorders characterized by thrombosis, primary arterial thrombotic complications of atherosclerotic disease, thrombosis secondary to vascular damage and inflammation, indications with a diffuse thrombotic/platelet consumption component, venous thrombosis, coronary arterial thrombosis, pathological effects of atherosclerosis and arteriosclerosis, chronic or acute states of hyper-aggregability, reocclusion of an artery or vein following fibrinolytic therapy.

5. The method according to claim 4, wherein said thrombosis are unstable angina, or myocardial infarction; said primary arterial thrombotic complications of atherosclerosis are thrombotic stroke, peripheral vascular disease, or myocardial infarction said thromboses secondary to vascular damage and inflammation are vasculitis, arteritis, glomerulonephritis or organ graft rejection; said indications with a diffuse thrombotic/platelet consumption component are disseminated intravascular coagulation, thrombotic thrombocytopenic purpura, hemolytic uremic syndrome, heparin-induced thrombocytopenia, pre-eclampsia or eclampsia; said venous thrombosis are deep vein thrombosis, veno-occlusive disease, or hematological conditions; and said coronary arterial thrombosis is associated with unstable angina, coronary angioplasty or acute myocardial infarction.

6. The method according to claim 5, wherein said pathological effects of atherosclerosis and arteriosclerosis are arteriosclerosis, acute myocardial infarction, chronic stable angina, unstable angina, transient ischemic attacks, strokes, peripheral vascular disease, arterial thrombosis, preeclampsia, embolism, restenosis or abrupt closure following angioplasty, carotid endarterectomy, or anastomosis of vascular grafts; said chronic or acute states of hyper-aggregability is caused by DIC, septicemia, surgical or infectious shock, post-operative trauma, post-partum trauma, thrombotic thrombocytopenic purpura, snake venom or immune diseases.

7. The method according to claim 1, wherein said conditions associated with increased platelet aggregation and/or platelet activation are produced by the contact of blood with an artificial device.

8. The method according to claim 7, wherein said artificial device is a hemodialysis instrument, a paracorporeal artificial lung and an extracorporeal membrane oxygenation device, an internal implantable artificial heart, an apheresis instrument used to remove or isolate a specific component of the blood and returning the remaining blood components to a donor.

9. The method according to claim 1, wherein said administering is systemic administration of said compound to a subject.

10. The method according to claim 9, wherein said systemic administration is oral administration.

11. A method for in vitro inhibiting the aggregation of platelets in blood or blood product, comprising the step of administering to the blood or blood product the compound according to claim 1, or a salt, solvate, or hydrate thereof.

12. A method of treating patients to inhibit platelet aggregation in a reversible manner, comprising the steps of: (a) providing a patient in need of rapid reversal of platelet aggregation inhibition; (b) administering a therapeutically effective amount of a compound of Formula I according to claim 1 to the patient; (c) submitting the patient to a procedure selected from the group consisting of: percutaneous coronary interventions, stent placement, balloon angioplasty, coronary atherectomy, coronary endarterectomy, carotid endarterectomy, thrombolytic theraphy, coronary or other vascular graft surgery, and dialysis, (d) discontinuing the administering of said compound to the patient; and (e) allowing the amount of said compound in the patient's blood to reduce to below an therapeutically effective amount.

13. The method according to claim 1, wherein said conditions are associated with procedures resulting in platelet aggregation, said conditions are selected from the group consisting of thrombotic complications of interventions to treat atherosclerotic disease, thrombotic complications resulting from surgical procedures, thrombotic complications resulting from mechanically-induced platelet activation, shunt occlusion, thrombosis secondary to vascular damage and inflammation, platelet adhesion associated with extracorporeal circulation, platelet activation associated with extracorporeal circulation, thrombotic complications associated with thrombolytic therapy, thrombotic complications associated with coronary and other angioplasty, and thrombotic complications associated with coronary artery bypass procedures.

14. The method according to claim 13, wherein said thrombotic complications of interventions to treat atherosclerotic disease are associated with procedures of angioplasty, endartectomy, or stent placement; said surgical procedures are coronary revascularization procedures, vascular graft surgery, tissue salvage following surgical or accidental trauma, or reconstructive surgery; said mechanical-induced platelet activation is caused by cardiopulmonary bypass resulting in microthromboembolism, platelet refractoriness, and thrombocytopenia; said thrombotic complications resulting from shunt occlusion are associated with procedures of renal dialysis or plasmapheresis.

15. The method according to claim 1, wherein said diseases are stroke or angina.

16. The method according to claim 4, wherein said diseases associated with platelet aggregation are disorders characterized by thrombosis, primary arterial thrombotic complications of atherosclerotic disease, thrombosis secondary to vascular damage and inflammation, indications with a diffuse thrombotic/platelet consumption component, venous thrombosis, coronary arterial thrombosis.

17. The method according to claim 1, wherein R_d′ is C_1-4alkyl or C_3-6cycloaklyl.

18. The method according to claim 1, wherein R_b is aryl, optionally bearing one or more substituents.

19. The method according to claim 17, wherein said aryl is phenyl, benzyl, or styryl.

20. The method according to claim 1, wherein R_b is aralkyl, optionally bearing one or more substituents.

21. The method according to claim 1, wherein R_g=R_f=R_d=H; R_d′ is C_1-4 alkyl, C_3-6 cycloalkyl; M is independently selected from the group consisting of: —H, halogen, —CF₃, C_1-4 alkyl, C_1-4 alkoxy, cyano, or amino; R_b is phenyl, benzyl, or styryl, optionally substituted.

22. The method according to claim 1, wherein said compound is

23. The method according to claim 22, wherein said compound is Compound 58, 60, or 62.

TECHNICAL FIELD

This invention relates to non-nucleotide compounds and methods of making and using such compounds in the prevention or treatment of diseases or conditions associated with platelet aggregation, including thrombosis, stroke and myocardial infarction in humans and other mammals, and for inhibition of platelet aggregation in blood and blood-related products.

BACKGROUND OF THE INVENTION

Hemostasis is the spontaneous process of arresting bleeding from damaged blood vessels. Upon injury, precapillary vessels contract within seconds, and thrombocytes, or blood platelets, bind to the exposed subendothelial matrix of an injured vessel by a process called platelet adhesion. Platelets also stick to each other in a phenomenon known as platelet aggregation to form stable platelet aggregates that quickly help stop or slow blood outflow from injured vessels.

An intravascular thrombus can result from pathological disturbances of hemostasis, or by the rupture of atherosclerotic plaques. Platelet adhesion and aggregation are critical events in intravascular thrombosis. Activated under conditions of high shear blood flow in diseased vessels or by the release of mediators from other circulating cells and damaged endothelial cells lining the vessel, platelets and other cells accumulate at a site of vessel injury to form a thrombus, and recruit more platelets to the developing thrombus. The thrombus can grow to sufficient size to block off arterial blood vessels. Thrombi can also form in areas of stasis or slow blood flow in veins. Venous thrombi can easily detach portions of themselves, creating emboli that travel through the circulatory system. This process can result in blockade of other vessels, such as pulmonary arteries. Blockages of this sort can result in pathological outcomes such as pulmonary embolism. Thus, arterial thrombi cause serious disease by local blockade, whereas the morbidity and mortality associated with venous thrombi arise primarily after distant blockade, or embolization. Conditions associated with pathological thrombus formation include venous thromboembolism, thrombophlebitis, deep vein thrombosis, arterial embolism, coronary and cerebral arterial thrombosis, unstable angina, myocardial infarction, stroke, transient ischemic attack, cerebral embolism, renal embolism and pulmonary embolism.

A number of converging pathways lead to platelet aggregation. Whatever the initial stimulus, the final common event is crosslinking of platelets by binding of fibrinogen to a membrane binding site, glycoprotein IIb/IIIa (GP IIb/IIIa, also known as integrin α _IIb β ₃ ). Antagonists of the GP IIb/IIIa receptor have been shown to produce potent antithrombotic effects (Ali, U.S. Pat. No. 6,037,343; Duggan, et al., U.S. Pat. No. 6,040,317). GP IIb/IIIa antagonists include function-blocking antibodies like Abciximab (ReoPro®), cyclic peptides and peptidomimetic compounds (The EPIC investigators; Califf, R. M., coordinating author, New Engl. J. Med. 330: 956-961 (1994); The IMPACT-II investigators, Lancet 349:1422-1428 (1997); The RESTORE investigators, Circulation 96: 1445-1453 (1997)). The clinical efficacy of some of these newer drugs, such as Abciximab, is impressive, but recent trials have found that these approaches are associated with an increased risk of major bleeding, sometimes necessitating blood transfusion (The EPIC investigators; Califf, R. M., coordinating author, New Engl. J. Med. 330: 956-961 (1994)). Also, administration of this class of antiplatelet agent appears to be limited to intravenous methods.

Thrombin can produce platelet aggregation independently of other pathways but substantial quantities of thrombin are unlikely to be present without prior activation of platelets by other mechanisms. Thrombin inhibitors, such as hirudin, are highly effective antithrombotic agents. However, functioning as both antiplatelet and anti-coagulant agents, thrombin inhibitors again can produce excessive bleeding (The TIMI 9a Investigators, Circulation, 90: 1624-1630 (1994); The GUSTO IIa Investigators, Circulation, 90: 1631-1637 (1994); Neuhaus, et al., Circulation, 90: 1638-1642 (1994)).

Various antiplatelet agents have been studied as inhibitors of thrombus formation. Some agents such as aspirin and dipyridamole have come into use as prophylactic antithrombotic agents, and others have been the subjects of clinical investigations. To date, therapeutic agents such as the disintegrins, and the thienopyridines ticlopidine (TICLID®) and clopidogrel (PLAVIX®) have been shown to have utility as platelet aggregation inhibitors, although they can produce a substantial number of side effects and have limited effectiveness in some patients. (Hass, et al., N. Engl. J. Med., 321: 501-507 (1989); Weber, et al., Am. J. Cardiol. 66: 1461-1468 (1990); Lekstrom and Bell, Medicine 70: 161-177 (1991)). In particular, the use of the thienopyridines in antiplatelet therapies has been shown to increase the incidence of potentially life threatening thrombotic thrombocytopenic purpura (Bennett, et al., N. Engl. J. Med, 342: 1771-1777 (2000)). Aspirin, which has a beneficial effect on the inhibition of platelet aggregation (Antiplatelet Trialists' Collaboration, Br. Med. J. 308: 81-106 (1994); Antiplatelet Trialists' Collaboration, Br. Med. J. 308: 159-168 (1994)), acts by inhibiting the synthesis of prostaglandins. Its well-documented, high incidence of gastric side effects, however, limits its usefulness in many patients. In addition, aspirin resistance has been observed in some individuals (McKee, et al., Thromb. Haemost. 88: 711-715 (2002)).

Many studies have demonstrated that adenosine 5′-diphosphate (ADP) plays a key role in the initiation and progression of arterial thrombus formation (Bernat, et al., Thromb. Haemostas. 70: 812-826 (1993)); Maffrand, et al., Thromb. Haemostas. 59: 225-230 (1988); Herbert, et al., Arterioscl. Thromb. 13: 1171-1179 (1993)). ADP induces inhibition of adenylyl cyclase and modulation of intracellular signaling pathways such as activation of phosphoinositide-3 kinase (PI3K), influx and mobilization of intracellular Ca ⁺² , secretion, shape change, and platelet aggregation (Dangelmaier, et al. Thromb Haemost. 85: 341-348 (2001)). ADP-induced platelet aggregation is triggered by its binding to specific receptors expressed in the plasma membrane of the platelet. There are at least three different P2 receptors expressed in human platelets: P2X ₁ , P2Y ₁ , and P2Y ₁₂ . The P2X ₁ receptor is a ligand-gated cation channel that is activated by ATP, resulting in a transient influx of extracellular calcium. This receptor has been implicated in the regulation of platelet shape change, and recent evidence suggests its participation in thrombus formation in small arteries under high shear forces. (Jagroop, et al., Platelets 14:15-20 (2003); Hechler, et al., J. Exp. Med. 198: 661-667 (2003)). The P2Y ₁ receptor is a G protein-coupled receptor that is activated by ADP, and is responsible for calcium mobilization from intracellular stores, platelet shape change and initiation of aggregation. The P2Y ₁₂ receptor, also referred to as the P2Y _ac and P2 _T receptor, is a G protein-coupled receptor that is activated by ADP and is responsible for inhibition of adenylyl cyclase and activation of PI3K. Activation of P2Y ₁₂ is required for platelet secretion and stabilization of platelet aggregates (Gachet, Thromb. Haemost. 86: 222-232 (2001); André, et al., J. Clin. Invest., 112: 398-406 (2003)).

ADP-induced platelet aggregation requires the simultaneous activation of both P2Y ₁ and P2Y ₁₂ receptors, and therefore, aggregation can be inhibited by blockade of either receptor. Several authors have demonstrated that ADP-induced aggregation is inhibited in a concentration-dependent manner by analogues of adenosine triphosphate (ATP). ATP, itself, is a weak and nonselective, but competitive, P2Y ₁ and P2Y ₁₂ receptor antagonist. Ingall, et al. ( J. Med. Chem. 42: 213-220 (1999)) have reported that modification of the polyphosphate side chain of ATP along with substitution of the adenine moiety at the C ² -position, resulted in compounds that inhibited the P2 _T receptor (or P2Y ₁₂ receptor). Zamecnik (U.S. Pat. No. 5,049,550) has disclosed a method for inhibiting platelet aggregation by administration of a diadenosine tetraphosphate-like compound, App(CH ₂ )ppA. Kim and Zamecnik (U.S. Pat. No. 5,681,823) have disclosed P ¹ , P ⁴ -(dithio)-P ² , P ³ -(monochloromethylene)-5′, 5′″-diadenosine-P ¹ , P ⁴ -tetraphosphate as an antithrombotic agent.

Nucleotide P2Y ₁₂ antagonists have been developed, however, there is still a need for compounds that have improved oral bioavailability and blood stability.

Thienopyridines, ticlopidine and clopidogrel react covalently with the P2Y ₁₂ receptor and produce irreversible platelet inhibition in vivo (Quinn and Fitzgerald, Circulation 100: 1667-1672 (1999); Geiger, et al., Arterioscler. Thromb. Vasc. Biol. 19: 2007-2011 (1999); Savi, et al., Thromb Haemost. 84: 891-896 (2000)). Patients treated with thienopyridines usually require 2-3 days of therapy to observe significant inhibition of platelet aggregation, however, and maximal inhibition usually is observed between 4 to 7 days after initiation of treatment. Also, the platelet inhibitory effect of thienopyridines persists up to 7-10 days after the therapy is discontinued, and both ticlopidine and clopidogrel produce a significant prolongation of the bleeding time (from 1.5 to 2-fold over control). Because of the prolonged effect of thienopyridines, these drugs need to be discontinued for 7 to 10 days prior to elective surgery, leaving the patient unprotected from a possible thrombotic event during that period. Recently, the association of thienopyridine treatment with events of thrombotic thrombocytopenic purpura has been reported (Bennett, et al., N. Engl. J. Med. 342: 1773-1777 (2000); Bennett, et al., Ann. Intern. Med. 128: 541-544 (1998)).

Derivatives of 5,7-disubstituted-1,2,3-triazolol[4,5-d]pyrimidin-3-yl-cyclo pentanes and -tetrahydrofurans have been disclosed as antagonists of the P2T- (or P2Y ₁₂ ) receptor on platelets (Cox, et al., U.S. Pat. No. 5,747,496, and related patents; Bonnert, et al., U.S. Pat. No. 6,297,232; WO 98/28300; Brown, et al., WO 99/41254; WO 99/05144; Hardern, et al. WO 99/05142; WO 01/36438; and Guile, et al. WO 99/05143) for use in the treatment of platelet aggregation disorders.

Guile, et al. (WO 00/04021) disclose the use of triazolo[4,5-d]pyrimidine compounds in therapy. Brown, et al. (U.S. Pat. No. 6,369,064) disclose the use of Triazolo(4,5-d)pyrimidine compounds in the treatment of myocardial infarction and unstable angina. Dixon, et al. (WO 02/096428) disclose the use of 8-azapurine derivatives in combination with other antithrombotic agents for antithrombotic therapy. Springthorpe discloses AZD6140 as a potent, selective, orally active P2Y ₁₂ receptor antagonist which is now in Phase I clinical trials (Abstracts of Papers, 225 ^th ACS National Meeting, New Orleans, La.; March, 2003; MEDI-016). WO 02/016381 discloses a method of preventing or treating diseases or conditions associated with platelet aggregation using mononucleoside polyphosphates and dinucleoside polyphosphates.

There is still a need in the areas of cardiovascular and cerebrovascular therapeutics, and in blood product preparation, purification, and storage, for selective, reversible inhibitors of platelet activation, which can be used in the prevention and treatment of thrombi or other aggregation-related problems.

SUMMARY OF THE INVENTION

This invention is directed to methods of preventing or treating diseases or conditions associated with platelet aggregation or where the aggregation of platelets inhibits treatment options. This invention is directed to methods of preventing or treating thrombosis and related disorders. This invention is further directed to methods of inhibiting platelet aggregation in blood and blood products comprising platelets, such as stored blood.

The method comprises administering to a mammalian subject or to a sample comprising blood or platelet-comprising material, a composition comprising one or more non-nucleotide P2Y ₁₂ receptor antagonist compound that effectively binds to P2Y ₁₂ receptors on platelets, preferably in a reversible manner, and thereby causes an inhibition of the ADP-induced platelet aggregation response in blood or in a platelet-comprising material. The compounds useful for the methods are compounds of general Formula I, III-XII, and/or tautomers thereof, and/or pharmaceutically-acceptable hydrates, solvates, and/or salts thereof.

The invention also provides novel compounds and pharmaceutical compositions. The compounds of Formulae I, and III-XII are useful in that they possess antagonist activity at platelet P2Y ₁₂ receptors.

Optionally, the compounds of this invention can be used in combination with other compounds useful for the treatment of platelet aggregation disorders or diseases.

DETAILED DESCRIPTION OF THE INVENTION

Definitions

When present, unless otherwise specified, the following terms are generally defined as, but are not limited to, the following:

Alkyl groups are from 1 to 12 carbons inclusively, either straight chained or branched, with or without unsaturation and with or without heteroatoms, are more preferably from 2 to 8 carbons inclusively, and most preferably 2 to 6 carbons inclusively.

Alkenyl groups are from 1 to 12 carbons inclusively, either straight or branched containing at least one double bond but may contain more than one double bond, with or without heteroatoms.

Alkynyl groups are from 1 to 12 carbons inclusively, either straight or branched containing at least one triple bond but may contain more than one triple bond, and additionally may contain one or more double bonded moieties, with or without heteroatoms.

Cycloalkyl groups from 3 to 12 carbons inclusively, more preferably from 3 to 10 carbons inclusively, and most preferably 3 to 6 carbons inclusively, with or without unsaturation, and with or without heteroatoms.

Aralkyl groups are from 1 to 8 carbons inclusively in the alkyl portion, are more preferably from 1 to 6 carbons inclusively in the alkyl portion, and most preferably are 1 to 4 carbons inclusively in the alkyl portion; as included in the alkyl definition above, the alkyl portion of an aralkyl group can include one or more positions of unsaturation such as a double bond or a triple bond in the chain when the chain includes two or more carbon atoms; the alkyl portion of an aralkyl group can also include one or more heteroatoms and/or substituents; the aryl portion of an aralkyl group can be a monocyclic or polycyclic moiety from 3 to 8 carbons inclusively per ring in the aryl portion, more preferably from 4 to 6 carbons inclusively per ring, and most preferably 5 to 6 carbons inclusively per ring; the aryl portion of an aralkyl group can also bear one or more substituents and/or heteroatoms.

Aryl groups are either monocyclic or polycyclic, are from 3 to 8 carbons inclusively per ring, are more preferably from 4 to 6 carbons inclusively per ring, and are most preferably 5 to 6 carbons inclusively per ring; aryl groups can also bear substituents and/or heteroatoms.

Heteroaralkyl groups are from 1 to 8 carbons inclusively in the alkyl portion, are more preferably from 1 to 6 carbons inclusively in the alkyl portion, and most preferably are 1 to 4 carbons inclusively in the alkyl portion; as included in the alkyl definition above, the alkyl portion of a heteroaralkyl group can include one or more positions of unsaturation such as a double bond or a triple bond in the chain when the chain includes two or more carbon atoms; the alkyl portion of a heteroaralkyl group can also include one or more heteroatoms and/or substituents; the heteroaryl portion of a heteroaralkyl group can be a monocyclic or polycyclic moiety from 3 to 8 carbons inclusively per ring in the heteroaryl portion and containing from 1 to 4 heteroatoms inclusively per ring, more preferably from 4 to 6 carbons inclusively per ring, and most preferably 5 to 6 carbons inclusively per ring; the heteroaryl portion of an heteroaralkyl group can also bear one or more substituents and/or heteroatoms.

Heteroaryl groups are either monocyclic or polycyclic, contain from 1 to 4 heteroatoms inclusively per ring, are from 3 to 8 atoms inclusively per ring, are more preferably from 4 to 6 atoms inclusively per ring, and are most preferably 5 to 6 atoms inclusively per ring; heteroaryl groups can also bear substituents and/or heteroatoms.

Substituents on the foregoing groups can be, but are not limited to, hydroxy, nitro, methoxy, fluoro, chloro, bromo, iodo, methyl, ethyl, propyl, butyl, thioalkyl, alkoxy, carboxyl, carboxamido, alkylsulfonyl, alkylsulfonylamino, sulfonamido, cyano, amino, substituted amino, trifluoromethyl, trifluoromethoxy, phenyl, pyridyl, imidazolyl, cyclopropyl, cyclopentyl, and cyclohexyl; and preferred heteroatoms are oxygen, nitrogen, and sulfur.

A desired substituent on a chain or ring (in place of a hydrogen at a position) is one selected from the given alkyl, aryl, halogen, aralkyl, carboxy, alkoxycarbonyl, hydroxyl, acyloxy, alkoxy, aryloxy or aralkoxy classes or from other classes, which provides a compound with good-to-excellent P2Y ₁₂ receptor-binding properties, but which does not yield a compound with undesirable properties like chemical instability in a formulation, or one with levels of toxicity that are not well-tolerated by a treated mammal, or especially, not well-tolerated by a human.

Diastereomers are stereoisomers (isomers of identical constitution but differing three-dimensional architecture), which do not bear a mirror-image relation to each other.

Pharmaceutically acceptable salts are salts that retain the desired biological activity of the parent compound and do not impart undesired toxicological effects. Pharmaceutically acceptable salt forms include various polymorphs as well as the amorphous form of the different salts derived from acid or base additions. The acid addition salts can be formed with inorganic or organic acids. Illustrative but not restrictive examples of such acids include hydrochloric, hydrobromic, sulfuric, phosphoric, citric, acetic, propionic, benzoic, napthoic, oxalic, succinic, maleic, malic, mesylic, adipic, lactic, tartaric, salicylic, methanesulfonic, 2-hydroxyethanesulfonic, toluenesulfonic, benzenesulfonic, camphorsulfonic, and ethanesulfonic acids. The pharmaceutically acceptable base addition salts can be formed with metal or organic counterions and include, but are not limited to, alkali metal salts such as sodium or potassium; alkaline earth metal salts such as magnesium or calcium; and ammonium or tetraalkyl ammonium salts, i.e., NX ₄ ⁺ (wherein X is C _1-4 ). Other salts such as hydrochlorides, hydrobromides, mesylates, sulfates, acetates, tartrates, etc., are also contemplated in this invention. Preferred counterions are monovalent ions such as NH ₄ ⁺ , sodium, lithium, potassium, chloride, bromide, bisulfate, and mesylate, with sodium, potassium, chloride and mesylate being most preferred due to ease of manufacture, stability, and physiological tolerance.

Solvates are addition complexes in which a compound is combined with a pharmaceutically acceptable cosolvent in some fixed proportion. Cosolvents include, but are not limited to, water, methanol, ethanol, 1-propanol, isopropanol, 1-butanol, isobutanol, tert-butanol, acetone, methyl ethyl ketone, acetonitrile, ethyl acetate, benzene, toulene, xylene(s), ethylene glycol, dichloromethane, 1,2-dichloroethane, N-methylformamide, N,N-dimethylformamide, N-methylacetamide, pyridine, dioxane, and diethyl ether. Hydrates are solvates in which the cosolvent is water. It is to be understood that the definition of the compound of the present invention encompasses all possible hydrates and solvates, in any proportion, which possess the stated activity.

P2Y ₁₂ Receptor Antagonist Compounds

The P2Y ₁₂ receptor antagonist compounds useful for preventing or treating diseases or conditions associated with platelet aggregation and/or platelet activation include compound of general Formula I, and/or tautomers thereof, or a pharmaceutically acceptable salt, solvate, or hydrate thereof:

wherein R _a and R _b are each independently selected from the group consisting of:

• hydrogen, C _1-8 alkyl, C _1-8 alkenyl, C _1-8 alkynyl, C _3-7 cycloalkyl, C _4-7 cycloalkenyl, aralkyl (including saturation and/or unsaturation in the alkylene portion), aryl, and saturated or unsaturated C _3-6 heterocycle; where all rings or chains optionally can bear one or more desired substituents; or
• R _a and R _b are taken together to form a ring of 3 to 7 members, with or without substitution, and with or without heteroatoms in place of ring carbon atoms;
• R _c =H, C _1-8 alkyl, C _3-7 cycloalkyl, aralkyl, aryl, or heterocycle, or R(CO)—;
• where R is selected from the group consisting of: C _1-8 alkyl, C _1-8 alkenyl, C _1-8 alkynyl, C _3-7 cycloalkyl, C _4-7 cycloalkenyl, aryl, aralkyl, heteroaryl, and saturated or unsaturated C _3-6 heterocycle; where all rings or chains optionally bear one or more desired substituents;
• G=O, S, or NR _d , where R _d is defined as below;
• R _d and R _d′ are independently selected from the group consisting of: H, C _1-8 alkyl, C _1-8 alkenyl, C _1-8 alkynyl, C _3-7 cycloalkyl, C _4-7 cycloalkenyl, C _4-11 alkylcycloalkyl, C _5-11 alkylcycloalkenyl, with 1 to 4 carbons in the alkyl portion, aralkyl (including saturation and/or unsaturation in the alkylene portion), aryl, heteroaryl, and saturated or unsaturated C _3-6 heterocycle; or
• R _d and R _d′ groups are taken together to form a ring of 4 to 7 members, with or without unsaturation and with or without heteroatoms in place of ring-carbon units; or
• R _d or R _d′ and R _c are taken together to form a ring of 4 to 7 members, with or without unsaturation and with or without heteroatoms in place of ring-carbon units;
• R _e =O or absent;
• R _f =H, halogen, C _1-8 alkyl, C _1-8 alkenyl, C _1-8 alkynyl, C _3-7 cycloalkyl, C _4-7 cycloalkenyl, C _4-11 alkylcycloalkyl, C _5-11 alkylcycloalkenyl, with 1 to 4 carbons in the alkyl portion, aryl, aralkyl (including saturation and/or unsaturation in the alkylene portion), heteroaryl, saturated or unsaturated C _3-6 heterocycle, —OH, C _1-6 alkoxy, aryloxy, —SH, C _1-6 thioalkyl, thioaryl, —[(CO)OR], —[(CO)NRR], amino, —N-substituted amino, or N,N-disubstituted amino; wherein each said substituent on said N-substituted-amino group, or N,N-disubstituted-amino-group of R _f is independently selected from the group consisting of:
• C _1-8 alkyl, C _1-8 alkenyl, C _1-8 alkynyl, C _3-7 cycloalkyl, C _4-7 cycloalkenyl, aryl, aralkyl, heteroaryl, C _3-6 heterocycle, —[(CO)R] and —[(CO)—NRR]; wherein each R is independently as defined above; or
• when R _f is —NRR, —[NH(CO)NRR], —[N(C _1-8 alkyl)(CO)NRR], —[N(aryl)(CO)NRR], or [N(aralkyl)(CO)NRR], the R groups of said —NRR unit (N,N-disubstituted-amino-group) in R _f can be taken together such that a ring of 3 to 7 members is formed, with or without heteroatoms in place of the ring-carbon units;
• J=N or C, with the proviso that when J=N, then R _g is absent;
• when J=C, R _g is selected from the group consisting of: —H, halogen, C _1-8 alkyl, C _1-8 alkenyl, C _1-8 alkynyl, C _3-7 cycloalkyl, C _4-7 cycloalkenyl, aralkyl, aryl, —OH, C _1-6 alkoxy, aryloxy, —SH, C _1-6 thioalkyl, thioaryl, —[(CO)OR], —[(CO)NRR], and —NRR; wherein each R is independently as defined above; or
• when R _g is —[(CO)NRR] or —NRR, the R groups of said —NRR unit (N,N-disubstituted-amino-group) in R _g are taken together such that a ring of 3 to 7 members is formed, with or without heteroatoms in place of the ring-carbon units;
• D is O, NH, N-acyl, N-alkyl, or C;
• A and B are each independently selected from the group consisting of: C, N, substituted N, O, S, S(O), SO ₂ , —C _1-3 alkylene-, —C _1-3 heteroalkylene, wherein each said —C _1-3 alkylene-unit of A and B independently can be saturated or unsaturated, and each carbon of a —C _1-3 alkylene-unit of B independently can be substituted with 0 to 2 fluorine groups, 0 to 1 methyl groups, 0 to 2 —[(CO)OR] groups, and 0 to 1 —(OR) groups, —CF ₂ —, —(CO)—; —NH(CO)—, —NR(CO)—, —(CO)NH—, —(CO)NR—, —NH(CO)NH—, —NH(CS)NH—, —N(NH)NH—, —N(NR)NH—, —NH(CO)O—, —NH(CS)O—, —O(CO)NH—, —O(CS)NH—, provided that no —S—S— or —O—O— bonds are formed by combination of the -A- and -B- groups; or
• A and/or B are absent;
• X=H, —OR, —COOH, —COOR, —SR, —S(O)RL, —S(O ₂ )RL, —SO ₃ H, —S(O ₂ )NRR, —S(O ₂ )NR(CO)RL, —NRR, —NR(CO)RL, —N[(CO)RL] ₂ , —NR(SO ₂ )RL, —NR(CO)NR(SO ₂ )RL, —NR(SO ₂ )NRR, or —NR(SO ₂ )NR(CO)RL; wherein L is:
• H, —CF ₃ , —CF ₂ CF ₃ , C _1-8 alkyl, C _1-8 alkenyl, C _1-8 alkynyl, C _3-7 cycloalkyl, C _4-7 cycloalkenyl, C _4-11 alkylcycloalkyl, C _5-11 alkylcycloalkenyl, with 1 to 4 carbons in the alkyl portion, saturated or unsaturated heteroaryl, aryl, aralkyl (including saturation and/or unsaturation in the alkylene portion), saturated or unsaturated C _3-6 heterocycle, C _1-6 alkoxy, aralkoxy, aryloxy, N,N-disubstituted-amino, N-substituted-amino, or unsubstituted-amino; where all rings or chains optionally bear one or more desired substituents; or
• when L is N-substituted-amino, or N,N-disubstituted-amino, each substituent of said amino group of L is selected from the group consisting of: C _1-8 alkyl, C _1-8 alkenyl, C _1-8 alkynyl, C _3-7 cycloalkyl, C _4-7 cycloalkenyl, aryl, heteroaryl, aralkyl, and C _3-6 heterocycle;
• when L is N,N-disubstituted-amino, the two substituents independently selected from the group above are taken together to form a ring of 3 to 7 members, wherein said formed ring thereon bears the remaining features of said selected substituents before said ring formation; optionally can be made for any one-carbon-unit within either or both of said C _1-3 alkylene units of A and B, provided that fewer than three said heteroatom-containing-unit for -one-carbon-unit substitutions on the -A-B- chain are made, no —S—S—, or —O—O— bonds are formed in the X-A-B- chain by said substitution or substitutions of a heteroatom-containing-unit for a -one-carbon-unit on the -A-B- chain, and no said heteroatom substitution is made such that the said replacement heteroatom connects directly to the tetrahydrofuran ring shown in Formula I;
• wherein the R groups of a —NRR unit (N,N-disubstituted-amino-group) in X optionally can be taken together such that a ring of 3 to 7 members is formed, with or without heteroatoms in place of the ring-carbon units;
• with the proviso that when X=H, then at least one of R _a or R _b must be H; or
• X is a group as provided in Formula II:

• wherein:
  • X ₆ is the attachment point to the moiety defined by A-B;
  • the ring defined by X ₁ -X ₆ is taken to mean a ring with or without unsaturation;
  • X ₁ -X ₆ are independently C, N, O, or S; and
  • when any of X ₁ -X ₅ is C, the carbon atom bears an H when doubly bonded in an unsaturated ring, or a substituent M, as defined below; or
  • when any of X ₁ -X ₅ is C, the carbon atom bears two H when singly bonded in a saturated ring, or one H plus one substituent M, or two substituents M without H, with the proviso that any such moiety with one or two M substituents is of sufficient chemical stability;
  • when any of X ₁ -X ₅ is N in an saturated ring, the nitrogen atom bears an H or substituents such as alkyl or acyl;
  • any of X ₁ -X ₅ can be absent, with the proviso that at least two of X ₁ -X ₅ are present, such that the ring described by X ₁ -X ₆ consists of at least three atoms;
  • with the provisos that no two adjacent atoms X ₁ -X ₆ can both be O or S, and that the ring shown in Formula II contains no more than four heteroatoms, and that the shown pendant —CO ₂ R _h unit in Formula II is a substituent on the ring described in Formula II;
  • p=0, 1, or 2;
  • r=0 or 1;
  • R _h is H, a physiologically-relevant cation forming a carboxylate salt, alkyl, aryl, or aralkyl, with the resultant moiety C(O)OR _h preferably having an adjacent relationship to the attachment point of A; preferably R _h is H or alkyl (such as ethyl):
  • M is selected from the group consisting of: —H, halogen (such as F, Cl, Br), —CF ₃ , C _1-8 alkyl, C _1-8 alkenyl, C _1-8 alkynyl, C _3-7 cycloalkyl, C _4-7 cycloalkenyl, aryl, aralkyl, heteroaryl, saturated or unsaturated C _3-6 heterocycle, —OH, cyano, saturated or unsaturated C _1-6 alkoxy, aralkoxy, aryloxy, —SH, C _1-6 thioalkyl, thioaryl, —[(CO)OR], —[(CO)NRR], amino, —N-substituted amino, and N,N-disubstituted amino; wherein each said substituent on said amino of M is independently selected from the group consisting of: C _1-8 alkyl, C _1-8 alkenyl, C _1-8 alkynyl, C _3-7 cycloalkyl, C _4-7 cycloalkenyl, aryl, aralkyl, heteroaryl, C _3-6 heterocycle, —[(CO)R], —[(CO)O—(C _1-8 alkyl)], and —[(CO)—NRR]; and

more than one moiety M can be present, either the same or different.

Preferably, the furanosyl moiety in Formula I has the 2′- and 3′-oxygen-groups in a cis-orientation relative to one another on the furanose ring. Further, a furanosyl moiety which supports a 2′,3′-acetal or -ketal group is, preferably, derived from ribose; other furanose derivatives can be used, however. A preferred stereochemical embodiment of this invention includes, but is not limited to (D)-ribose-(2′,3′-acetal or -ketal) compounds of Formula I, such as found in acetals derived from (−)-adenosine.

In one embodiment of the method, the compound of Formula I is selected from the group consisting of:

4-{2,2-Dimethyl-6-[6-(3-phenyl-ureido)-purin-9-yl]-tetrah ydro-furo[3,4-d][1,3]dioxol-4-ylmethoxy}-isophthalic acid (1), 5-Amino-2-{2-benzyl-6-[6-(3-phenyl-ureido)-purin-9-yl]-tetra hydro-furo[3,4-d][1,3]dioxol-4-ylmethoxy}-benzoic acid (2), 3-{2,2-Dimethyl-6-[6-(3-phenyl-ureido)-purin-9-yl]-tetrahydr o-furo[3,4-d][1,3]dioxol-4-ylmethoxy}-isoxazole-5-carboxylic acid (3), 4-{2,2-Dimethyl-6-[6-(3-phenyl-ureido)-purin-9-yl]-tetrahydr o-furo[3,4-d][1,3]dioxol-4-ylmethoxy}-benzoic acid (4), 5-Amino-2-{2,2-dimethyl-6-[6-(3-phenyl-ureido)-purin-9-yl]-t etrahydro-furo[3,4-d][1,3]dioxol-4-ylmethoxy}-N-hydroxy-benz amide (5), 5-Amino-2-{2-benzyl-6-[6-(3-phenyl-ureido)-purin-9-yl]-tetra hydro-furo[3,4-d][1,3]dioxol-4-ylmethoxy}-N-hydroxy-benzamid e (6), 6-{2,2-Dimethyl-6-[6-(3-phenyl-ureido)-purin-9-yl]-tetrahydr o-furo[3,4-d][1,3]dioxol-4-ylmethoxy}-nicotinamide (7), 6-{2,2-Dimethyl-6-[6-(3-phenyl-ureido)-purin-9-yl]-tetrahydr o-furo[3,4-d][1,3]dioxol-4-ylmethoxy}-nicotinic acid (8), 2-{2,2-Dimethyl-6-[6-(3-phenyl-ureido)-purin-9-yl]-tetrahydr o-furo[3,4-d][1,3]dioxol-4-ylmethoxy}-nicotinic acid (9), 5-Chloro-6-{2,2-dimethyl-6-[6-(3-phenyl-ureido)-purin-9-yl]- tetrahydro-furo[3,4-d][1,3]dioxol-4-ylmethoxy}-nicotinic acid (10), 1-{9-[6-(3-Hydroxy-pyridin-2-yloxymethyl)-2,2-dimethyl-tetra hydro-furo[3,4-d][1,3]dioxol-4-yl]-9H-purin-6-yl}-3-phenyl-u rea (11), 6-Chloro-2-{2,2-dimethyl-6-[6-(3-phenyl-ureido)-purin-9-yl]- tetrahydro-furo[3,4-d][1,3]dioxol-4-ylmethoxy}-5-fluoro-nico tinic acid (12), 2-{2-Cyclohexyl-6-[6-(3-phenyl-ureido)-purin-9-yl]-tetrahydr o-furo[3,4-d][1,3]dioxol-4-ylmethoxy}-nicotinic acid (13), 2-[6-[6-(3-Phenyl-ureido)-purin-9-yl]-2-(2-trifluoromethyl-p henyl)-tetrahydro-furo[3,4-d][1,3]dioxol-4-ylmethoxy]-nicoti nic acid (14), 2-{2-(3,4-Dihydro-1H-naphthalenyl)-6-[6-(3-cyclopentyl-ureid o)-purin-9-yl]-tetrahydro-furo[3,4-d][1,3]dioxol-4-ylmethoxy }-nicotinic acid (15), 2-{2-(4-Acetylamino-phenyl)-6-[6-(3-cyclopentyl-ureido)-puri n-9-yl]-tetrahydro-furo[3,4-d][1,3]dioxol-4-ylmethoxy}-nicot inic acid (16), 2-{2-Phenyl-6-[6-(3-phenyl-ureido)-purin-9-yl]-tetrahydro-fu ro[3,4-d][1,3]dioxol-4-ylmethoxy}-nicotinic acid (17), 2-{2-Biphenyl-3-yl-6-[6-(3-phenyl-ureido)-purin-9-yl]-tetrah ydro-furo[3,4-d][1,3]dioxol-4-ylmethoxy}-nicotinic acid (18), 2-{2-Naphthalen-2-yl-6-[6-(3-phenyl-ureido)-purin-9-yl]-tetr ahydro-furo[3,4-d][1,3]dioxol-4-ylmethoxy}-nicotinic acid (19), 2-{2-(2-Bromo-phenyl)-6-[6-(3-ethyl-ureido)-purin-9-yl]-tetr ahydro-furo[3,4-d][1,3]dioxol-4-ylmethoxy}-nicotinic acid (20), 2-{2-Benzo[b]thiophen-3-yl-6-[6-(3-phenyl-ureido)-purin-9-yl ]-tetrahydro-furo[3,4-d][1,3]dioxol-4-ylmethoxy}-nicotinic acid (21), 2-{6-[6-(3-Cyclopentyl-ureido)-purin-9-yl]-2-phenethyl-tetra hydro-furo[3,4-d][1,3]dioxol-4-ylmethoxy}-nicotinic acid (22), 2-{6-[6-(3-Cyclopentyl-ureido)-purin-9-yl]-2-phenethyl-tetra hydro-furo[3,4-d][1,3]dioxol-4-ylmethoxy}-nicotinic acid (23), 2-{6-[6-(3-Hexyl-ureido)-purin-9-yl]-2-phenyl-tetrahydro-fur o[3,4-d][1,3]dioxol-4-ylmethoxy}-nicotinic acid (24), 2-{2-Biphenyl-4-yl-6-[6-(3-hexyl-ureido)-purin-9-yl]-tetrahy dro-furo[3,4-d][1,3]dioxol-4-ylmethoxy}-nicotinic acid (25), 2-{6-[6-(3-Ethyl-ureido)-purin-9-yl]-2-phenylethynyl-tetrahy dro-furo[3,4-d][1,3]dioxol-4-ylmethoxy}-nicotinic acid (26), 2-{6-[6-(3-Ethyl-ureido)-purin-9-yl]-2-phenethyl-tetrahydro- furo[3,4-d][1,3]dioxol-4-ylmethoxy}-nicotinic acid (27), 2-{6-[6-(3-Cyclopentyl-ureido)-purin-9-yl]-2-p-tolyl-tetrahy dro-furo[3,4-d][1,3]dioxol-4-ylmethoxy}-nicotinic acid (28), 2-{2-(2-indanonyl)-6-[6-(3-phenyl-ureido)-purin-9-yl]-tetrah ydro-furo[3,4-d][1,3]dioxol-4-ylmethoxy}-nicotinic acid (29), 2-{6-[6-(3-Ethyl-ureido)-purin-9-yl]-2-phenyl-tetrahydro-fur o[3,4-d][1,3]dioxol-4-ylmethoxy}-nicotinic acid (30), 2-{2-tert-Butyl-6-[6-(3-phenyl-ureido)-purin-9-yl]-tetrahydr o-furo[3,4-d][1,3]dioxol-4-ylmethoxy}-nicotinic acid (31), 3-({2,2-Dimethyl-6-[6-(3-phenyl-ureido)-purin-9-yl]-tetrahyd ro-furo[3,4-d][1,3]dioxole-4-carbonyl}-amino)-benzoic acid (32), 2-Benzyl-6-[6-(3-phenyl-ureido)-purin-9-yl]-tetrahydro-furo[ 3,4-d][1,3]dioxole-4-carboxylic acid (33), 1-{2-Benzyl-6-[6-(3-ethyl-ureido)-purin-9-yl]-tetrahydro-fur o[3,4-d][1,3]dioxole-4-carbonyl}-pyrrolidine-2-carboxylic acid (34), 1-{6-[6-(3-Benzyl-ureido)-purin-9-yl]-2-phenyl-tetrahydro-fu ro[3,4-d][1,3]dioxole-4-carbonyl}-pyrrolidine-2-carboxylic acid (35), 1-{2-Benzyl-6-[6-(3-cyclopentyl-ureido)-purin-9-yl]-tetrahyd ro-furo[3,4-d][1,3]dioxole-4-carbonyl}-pyrrolidine-2-carboxy lic acid (36), N-{2-Benzyl-6-[6-(3-phenyl-ureido)-purin-9-yl]-tetrahydro-fu ro[3,4-d][1,3]dioxole-4-carbonyl}-methanesulfonamide (37), 1-{6-[6-(3-Cyclopentyl-ureido)-purin-9-yl]-2-phenyl-tetrahyd ro-furo[3,4-d][1,3]dioxole-4-carbonyl}-pyrrolidine-2-carboxy lic acid (38), 1-{2-Phenyl-6-[6-(3-phenyl-ureido)-purin-9-yl]-tetrahydro-fu ro[3,4-d][1,3]dioxole-4-carbonyl}-pyrrolidine-2-carboxylic acid (39), 1-{2-Benzo[b]thiophen-3-yl-6-[6-(3-hexyl-ureido)-purin-9-yl] -tetrahydro-furo[3,4-d][1,3]dioxole-4-carbonyl}-pyrrolidine- 2-carboxylic acid (40), 1-{6-[6-(3-Benzyl-ureido)-purin-9-yl]-2-naphthalen-2-yl-tetr ahydro-furo[3,4-d][1,3]dioxole-4-carbonyl}-pyrrolidine-2-car boxylic acid (41), 1-(2-Benzyl-6-{6-[3-(2-phenyl-cyclopropyl)-ureido]-purin-9-y l}-tetrahydro-furo[3,4-d][1,3]dioxole-4-carbonyl)-pyrrolidin e-2-carboxylic acid (42), 1-{2-Benzyl-6-[6-(3-hexyl-ureido)-purin-9-yl]-tetrahydro-fur o[3,4-d][1,3]dioxole-4-carbonyl}-pyrrolidine-2-carboxylic acid (43), 1-{2-(2,4-Difluoro-phenyl)-6-[6-(3-phenyl-ureido)-purin-9-yl ]-tetrahydro-furo[3,4-d][1,3]dioxole-4-carbonyl}-pyrrolidine -2-carboxylic acid (44), 2-({2-Benzyl-6-[6-(3-phenyl-ureido)-purin-9-yl]-tetrahydro-f uro[3,4-d][1,3]dioxole-4-carbonyl}-amino)-3-hydroxy-propioni c acid (45), 3-{2,2-Dimethyl-6-[6-(3-phenyl-ureido)-purin-9-yl]-tetrahydr o-furo[3,4-d][1,3]dioxol-4-yl}-acrylic acid methyl ester (46), 3-{2,2-Dimethyl-6-[6-(3-phenyl-ureido)-purin-9-yl]-tetrahydr o-furo[3,4-d][1,3]dioxol-4-yl}-propionic acid methyl ester (47), 3-(3-{2,2-Dimethyl-6-[6-(3-phenyl-ureido)-purin-9-yl]-tetrah ydro-furo[3,4-d][1,3]dioxol-4-yl}-propionylamino)-benzoic acid (48), 1-(3-{2,2-Dimethyl-6-[6-(3-phenyl-ureido)-purin-9-yl]-tetrah ydro-furo[3,4-d][1,3]dioxol-4-yl}-propionyl)-pyrrolidine-2-c arboxylic acid (49), and 3-{2,2-Dimethyl-6-[6-(3-phenyl-ureido)-purin-9-yl]-tetrahydr o-furo[3,4-d][1,3]dioxol-4-yl}-propionic acid (50). The exemplified compounds named above can be in the forms depicted below, or can be pharmaceutically-acceptable salts, -hydrates, or -solvates thereof, where chemically appropriate.

In one embodiment of the present invention, when R _a and R _b are not identical, the compounds depicted in the following structures falling under the definitions of Formulae III-XII represent either one of the two possible diastereomers (which arise from the resultant chiral carbon of the acetal) in pure form, or a mixture of the two diastereomers in any proportion. As a practical matter however, the compounds as depicted represent the pure forms of the diastereomers. Diastereomers are distinct compounds, each with potentially different chemical and biological properties; thus pure forms are preferred as pharmaceutical agents. In addition, there are generally reasons, including but not limited to, the ease of chemical synthesis or separation, chemical or biological stabilility, toxicity, pharmacokinetic or pharmacodynamic properties in living systems, and the like, to choose between the two possible isomers. While it is possible to resolve such diastereomeric mixtures using chiral chromatographic methods, more preferred is the synthesis of a single diastereomer.

Depending on the acetal in question, the synthesis of a single diastereomer can be achieved in several ways. In some cases, one diastereomer can be selectively generated over the other by carrying out the acetal-forming reaction at a low temperature (such as below 0° C., for example, from −10 to −30° C.). In other cases, a mixture of two diastereomers having different acetal stabilities can be subjected to aqueous acidic conditions, which leads to decomposition of the less-stable diastereomer, while leaving the more stable diastereomer intact. In general, the single diastereomer that survives the decomposition is preferred, since chemical stability is an important attribute for a pharmaceutical product. These principles are exemplified and illustrated in the following compound examples, but as they can be reasonably expanded to related structures; the specific example should not be taken as limiting.

In one embodiment of the present invention, the compound of Formula I is a compound of Formula III:

• wherein R _a , R _b , R _c , G, R _d , R _d ′, R _e , R _f , J, R _g , and R _h are as defined in Formulae I and II;
• A ₁ is O or CH ₂ ;
• D is O or CH ₂ ;
• X ₁ is selected from the group consisting of: N (nitrogen) and C-M; and
• M is independently selected from the group consisting of: —H, halogen, —CF ₃ , C _1-8 alkyl, cyano, C _1-8 alkenyl, C _1-8 alkynyl, C _3-7 cycloalkyl, C _3-7 cycloalkenyl, aryl, aralkyl (including saturation and/or unsaturation in the alkylene portion), heteroaryl, saturated or unsaturated C _2-6 heterocycle, —OH, saturated or unsaturated C _1-6 alkoxy, aralkoxy, aryloxy, —SH, C _1-6 thioalkyl, thioaryl, —[(CO)OR], —[(CO)NRR], amino, —N-substituted amino, and N,N-disubstituted amino; wherein each said substituent on said amino of M is independently selected from the group consisting of: C _1-8 alkyl, C _3-7 cycloalkyl, aryl, aralkyl, heteroaryl, C _2-6 heterocycle, —[(CO)R], —[(CO)O—(C _1-8 alkyl)], and —[(CO)—NRR]; and when M is —[(CO)NRR], —[NH(CO)NRR], —[N(C _1-8 alkyl)(CO)NRR], —[N(aryl)(CO)NRR], or —[N(aralkyl)(CO)NRR], the R groups of any said —NRR unit (N,N-disubstituted-amino group) in M are optionally taken together such that a ring of 3 to 7 members is formed, with or without heteroatoms in place of the ring-carbon units.

Particularly useful compounds of Formula III are where the R _h =H or alkyl.

Preferred compounds of Formula III are:

wherein G=A ₁ =D=O;

R _a =R _c =R _d =R _f =R _g =R _h =H;

R _d′ =C _1-4 alkyl, or C _3-6 cycloalkyl;

R _e is absent;

X ₁ =C or N;

R _b =phenyl, benzyl, or styryl;

M=H, halogen, C _1-4 alkyl, C _1-4 alkoxy, CF ₃ , cyano, or amino.

Some of the preferred compounds falling under the definition of Formula III are:

In another embodiment of the present invention, the compound of Formula I is a compound of Formula IV:

• wherein R _a , R _b , R _c , G, D, R _d , R _d′ , R _e , R _f , J, M, R _g and R _h are as defined in Formulae I and II;
• q ₁ and q ₂ are 0, 1, or 2;
• the M and —CO ₂ R _h groups are independently and optionally attached to any carbon of the pyrrolidine ring; and
• when M is attached to a carbon that is bonded to the pyrrolidine nitrogen atom (alpha position), then M is not a halogen, hydroxyl, sulfhydryl, or amino group.

Particularly useful groups of compounds are those of Formula IV where R _h is H or alkyl and/or M is H or alkyl.

Preferred compounds of Formula IV are wherein:

q ₁ is 1 or 2;

q ₂ is 0 or 1;

G=O;

D=O or C;

R _a =R _c =R _d =R _f =R _g =H;

R _e is absent;

R _h =H or ethyl;

R _d′ =C _1-4 alkyl, or C _3-6 cycloalkyl;

R _b =phenyl, benzyl, or styryl;

M=H or C _1-4 alkyl.

Some of the preferred compounds falling under the definition of Formula IV are:

In another embodiment of the present invention, the compound of Formula I is a compound of Formula V:

• wherein R _a , R _b , R _c , G, D, R _d , R _d′ , R _e , R _f , J, M, X ₁ , R _g and R _h are as defined in Formulae I and II;
• A ₂ is C, O, S, S(O), SO ₂ , or N, where C can be substituted with H or alkyl, and N can be substituted with H, alkyl, or acyl; or
• A ₂ is absent.

Preferred compounds of Formula V are wherein:

• G=O;
• D=O or C;
• R _a =R _c =R _d =R _f =R _g =H;
• R _e is absent;
• R _h =H or ethyl;
• R _d′ =C _1-4 alkyl, or C _3-6 cycloalkyl;
• A ₂ is C, O, NH, N-methyl, N-acetyl, or absent;
• X ₁ =C or N;
• R _b =phenyl, benzyl, or styryl; and
• M=H, halogen, C _1-4 alkyl, C _1-4 alkoxy, CF ₃ , cyano, or amino.

Some of the preferred compounds falling under the definition of Formula V are:

In another embodiment of the method, the compound is a compound of Formula VI:

wherein:

• R _a , R _b , R _c , G, D, R _d , R _d′ , R _e , R _f , J, M, X ₁ , R _g and R _h are as defined in Formulae I and II;
• A ₃ is C, where C can be substituted with H or alkyl; or
• A ₃ is absent;
• R _i is H or alkyl.

Preferred compounds of Formula VI are wherein:

• G=D=O;
• R _a =R _c =R _d =R _e =R _f =R _g =R _h =R _i =H;
• R _d′ =C _1-4 alkyl, or C _3-6 cycloalkyl;
• A ₃ =CH ₂ , or absent;
• X ₁ =C or N;
• R _b =phenyl, benzyl, or styryl; and
• M=H, halogen, C _1-4 alkyl, C _1-4 alkoxy, CF ₃ , cyano, or amino.

Some of the preferred compounds falling under the definition of Formula VI are:

In another embodiment of the present invention, the compound of Formula I is a compound of Formula VII:

wherein:

• R _a , R _b , R _c , G, D, R _d , R _d′ , R _e , R _f , J, R _g and R _h are as defined in Formulae I and II;
• q ₁ and q ₂ are independently 0, 1, or 2;
• A ₂ is as previously defined for Formula V, with the proviso that when q ₁ and/or q ₂ are 0 and D=O, A ₂ is C; or
• A ₂ is absent.

Preferred compounds of Formula VII are wherein:

• G=D=O;
• R _a =R _c =R _d =R _f =R _g =H;
• R _e is absent;
• R _h =H or ethyl;
• R _d′ =C _1-4 alkyl, or C _3-6 cycloalkyl;
• A ₂ =CH ₂ , O, NH, N-methyl, N-acetyl, or absent;
• q ₁ and q ₂ =0 or 1; and
• R _b =phenyl, benzyl, or styryl.

Some of the preferred compounds falling under the definition of Formula VII are:

In another embodiment of the present invention, the compound of Formula I is a compound of Formula VIII:

wherein:

• R _a , R _b , R _c , G, D, R _d , R _d′ , R _e , R _f , J, R _g and R _h are as defined in Formulae I and II;
• q ₃ is 1, 2, or 3; and
• R _i is H or alkyl.

Preferred compounds of Formula VIII are wherein:

• G=D=O;
• R _a =R _c =R _d =R _f =R _g =H;
• R _e is absent;
• R _h =H or ethyl;
• R _i is H or methyl;
• R _d′ =C _1-4 alkyl, or C _3-6 cycloalkyl;
• q ₃ =1 or 2;
• R _b =phenyl, benzyl, or styryl.

Some of the preferred compounds falling under the definition of Formula VIII are:

In another embodiment of the present invention, the compound of Formula I is a compound of Formula IX:

wherein:

• R _a , R _b , R _c , G, D, R _d , R _d′ , R _e , R _f , J, R _g and R _h are as defined in Formulae I and II;
• A ₄ and A ₆ are independently C, N, O, or S, with the proviso that A ₄ can be absent;
• G′ is O, or S;
• such that the moiety described by A ₄ /C(G′)/A ₆ is an amide, thioamide, carbamate, thiocarbamate, urea, thiourea, ketone, or thioketone;
• q ₁ is 0, 1, or 2.

Preferred compounds of Formula IX are wherein:

• G=G′=O;
• A ₄ and A ₆ are independently C, N, or O;
• R _a =R _c =R _d =R _e =R _f =R _g =R _h =H;
• R _d′ =C _1-4 alkyl, or C _3-6 cycloalkyl;
• q ₁ =1; and
• R _b =phenyl, benzyl, or styryl.

Some of the preferred compounds falling under the definition of Formula IX are:

In another embodiment of the present invention, the compound of Formula I is a compound of Formula X:

wherein:

• R _a , R _b , R _c , G, D, R _d , R _d′ , R _e , R _f , J, M, X ₁ , R _g and R _h are as defined in Formulae I and II;
• G′ is O or S;
• A ₆ is C, N, O, S, or absent; and
• R _i is H or alkyl;
• such that the moiety described by A ₆ /C(G′)/NR _i is an amide, thioamide, carbamate, thiocarbamate, urea, or thiourea.

Preferred compounds of Formula X are wherein:

• G=G′=O;
• D=O or C;
• R _a =R _c =R _d =R _f =R _g =R _h =H;
• R _e is absent:
• R _i =H or methyl;
• R _d′ =C _1-4 alkyl, or C _3-6 cycloalkyl;
• A ₆ =CH ₂ , O, NH, or absent;
• X ₁ =C or N;
• R _b =phenyl, benzyl, or styryl; and
• M=H, halogen, C _1-4 alkyl, C _1-4 alkoxy, CF ₃ , cyano, or amino.

Some of the preferred compounds falling under the definition of Formula X are:

In another embodiment of the present invention, the compound of Formula I is a compound of Formula XI:

wherein:

• R _a , R _b , R _c , G, D, R _d , R _d′ , R _e , R _f , J, M, R _g and R _h are as defined in Formulae I and II;
• R _i is H or alkyl;
• G′ is O or S, such that the moiety C(G′)-NR _i is an amide or thioamide; and
• X ₁ is C or N.

Preferred compounds of Formula XI are wherein:

• G=G′=O;
• D=O or C;
• R _a =R _c =R _d =R _f =R _g =R _h =H;
• R _e is absent;
• R _i =H or methyl;
• R _d′ =C _1-4 alkyl, or C _3-6 cycloalkyl;
• X ₁ =C or N;
• R _b =phenyl, benzyl, or styryl; and
• M=H, halogen, C _1-4 alkyl, C _1-4 alkoxy, CF ₃ , cyano, or amino.

Some of the preferred compounds falling under the definition of Formula XI are:

In another embodiment of the present invention, the compound of Formula I is a compound of Formula XII:

wherein:

• R _a , R _b , R _c , G, D, R _d , R _d′ , R _e , R _f , J, M, R _g and R _h are as defined in Formulae I and II;
• X ₁ , X ₂ , X ₄ , X ₅ , and X ₆ are taken to mean a ring with or without unsaturation and are independently selected from the group consisting of: N, C, S, or O; and
• X ₁ -X ₆ are taken to mean a ring of from three to five atoms;
• q ₁ and q ₂ are independently 0, 1, or 2;
• A ₂ is C, O, S, S(O), SO ₂ , or N, or
• A ₂ is absent;
• such that when q ₁ and q ₂ =0 and A ₂ is absent, the ring described by X ₁ /X ₂ /X ₄ /X ₅ /X ₆ is directly bonded to the 4′ position of the ribose.

Preferred compounds of Formula XII are wherein:

• G=O;
• D=O or C;
• R _a =R _c =R _d =R _f =R _g =R _h =H;
• R _e is absent;
• q ₁ and q ₂ =0 or 1;
• A ₂ =CH ₂ , O, NH, or absent;
• R _d′ =C _1-4 alkyl, or C _3-6 cycloalkl;
• R _b =phenyl, benzyl, or styryl; and
• M=H.

Some of the preferred compounds falling under the definition of Formula XII are: